GB2065654A - Halogenation of 2-fluoroaniline - Google Patents
Halogenation of 2-fluoroaniline Download PDFInfo
- Publication number
- GB2065654A GB2065654A GB8040291A GB8040291A GB2065654A GB 2065654 A GB2065654 A GB 2065654A GB 8040291 A GB8040291 A GB 8040291A GB 8040291 A GB8040291 A GB 8040291A GB 2065654 A GB2065654 A GB 2065654A
- Authority
- GB
- United Kingdom
- Prior art keywords
- fluoroaniline
- dimethylformamide
- brominating
- bromo
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 230000026030 halogenation Effects 0.000 title claims description 3
- 238000005658 halogenation reaction Methods 0.000 title claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 12
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 claims abstract description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 9
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960002390 flurbiprofen Drugs 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical group CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000031709 bromination Effects 0.000 claims description 6
- 238000005893 bromination reaction Methods 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- CSFDTBRRIBJILD-UHFFFAOYSA-N 4-chloro-2-fluoroaniline Chemical compound NC1=CC=C(Cl)C=C1F CSFDTBRRIBJILD-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- YJLXEKFYZIBUPJ-UHFFFAOYSA-N 2,4-dibromo-6-fluoroaniline Chemical compound NC1=C(F)C=C(Br)C=C1Br YJLXEKFYZIBUPJ-UHFFFAOYSA-N 0.000 claims description 2
- ALZFPYUPNVLVQM-UHFFFAOYSA-N 2-bromo-6-fluoroaniline Chemical compound NC1=C(F)C=CC=C1Br ALZFPYUPNVLVQM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001448 anilines Chemical class 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 238000003556 assay Methods 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000005191 phase separation Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for brominating or chlorinating 2-fluoroaniline in a solvent, in which the solvent comprises dimethylformamide or dimethylacetamide. For example, 4-bromo-2- fluoroaniline can be prepared by reacting 2-fluoroaniline with bromantin in the presence of dimethylformamide. The product can be used as an intermediate in the preparation of flurbiprofen.
Description
SPECIFICATION
Halogenation of 2-fluoroaniline
In our Patent Applications Nos. 80/40295 and 80/ 40293 filed on even date herewith (Agents References GJE 6180/198 and GJE 6180/199) claiming priority from US Patent Applications Nos. 105,061 and 105,062, we have described and claimed a method for coupling aniline compounds to benzene compounds to form biphenyl compounds, and methods for converting aromatic, including the biphenyl, compounds to 2-arylpropionic acids. Such acids have valuable therapeutic properties.
A particularly valuable anti-inflammatory agent of the type described is 2-(2-fluoro-4biphenylyl)propionic acid which is also known as flurbiprofen. By the methods described above, this compound can be prepared from 4-halo-2fluoroanilines via 4-halobiphenyls.
U. S. Patent Specification No. 3,987,057 discloses the bromination of 2-fluoroaniline and cites, for example, Wommack etal., J. Het. Chem. 6, 243 (1969). The first report that 4-bromo-2-fluoroaniline is useful as a starting material appears in Kuroda et al., Chem. Abstr. 78,43571q (1973).
According to the present invention, a process for brominating or chlorinating 2-fluoroaniline is conducted in a solvent which comprises dimethylformamide or dimethylacetamide. By the process of the invention, 4-bromo-2-fluoroaniline may be prepared by reacting 2-fluoroaniline with a brominating agent and 4-chloro-2-fluoroaniline may be prepared by reacting 2-fluoroaniline with a chlorinating agent.
The preferred brominating agents are Nbromoamides or N-bromoimides. A particularly preferred brominating agent is dibromantin, i.e. 1,3- dibromo-5,5-dimethylhydantoin. The use of dibromantin in dimethylformamide in the process of the invention can provide nearly quantitative results, with unusually high selectivity at the 4-position.
If desired, a brominating agent such as Nbromoacetamide may be prepared in situ in dimethylformamide. Further possible brominating agent is N-bromosuccinimide.
Bromination of 2-fluoroaniiine may be accomplished by dropwise addition of a solution of a brominating agent to a solution of 2-fluoroaniline under conditions given by Wommack etal., J. Het.
Chem. 6,243 (1969) (see above). Temperatures of from 0 to -50, preferably -23 to -34, "C are necessary to obtain the selective 4-position bromination with minimal formation of a dibrominated product.
The 4-bromo-2-fluoroaniline produced can be obtained from the reaction mixture by conventional means such as extraction, chromatography, distillation and combination of these.
Chlorination may be accomplished in a comparable manner.
The following Example illustrates the invention.
Example
37.5 ml of dimethylformamide are added to 36.5 g (0.125 mole, based on assay of 97.7%) of 1,3dibromo-5,5-dimethylhydantoin under nitrogen in a dropping funnel. The mixture is stirred until the solids dissolve, and then the light yellow solution is added dropwise over 55 minutes to a solution of 24.1 ml of (0.250 mole) of 2-fluoroaniline in 30 ml of DMF, which is kept at -34 to -23 C with a Dry Ice-acetone bath. The dropping funnel is rinsed with 5 ml of methylene chloride which is also added to the reaction. The reaction mixture is poured into a separating funnel containing 27 ml of methylene chloride, 128 ml of heptane, 1 1g of 50% NaOH, and 120 ml of water.After phase separation, the aqueous layer is extracted with 50 ml of 20% methylene chloride in heptane, and the combined organic extracts are washed with 3 x 100 ml of water.
Evaporation of the organic solution to constant weight gives 46.4 grams (98% of theory) of an oil.
Gas liquid chromatographic analysis gives the following chemical yields: 4-bromo-2-fluoroaniiine, 94%; 2-fluoroaniline,0.2%; 2-bromo-6-fluoroaniline, 0.3%; 4,6-dibromo-2 fluoroaniline, 0%.
1. A process for brominating or chlorinating 2-fluoroaniline in a solvent, in which the solvent comprises dimethylformamide or dimethylacetamide.
2. A process for preparing 4-bromo-2fluoroaniline, which comprises brominating 2fluoroaniline in a solvent comprising dimethylformamide or dimethylacetamide.
3. A process for preparing 4-chloro-2fluoroaniline, which comprises chlorinating 2fluoroaniline in a solvent comprising dimethylformamide or dimethylacetamide.
4. A process according to claim 2 in which the brominating agent is dibromantin.
5. A process according to claim 1 substantially as described in the Example.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (5)
1. A process for brominating or chlorinating 2-fluoroaniline in a solvent, in which the solvent comprises dimethylformamide or dimethylacetamide.
2. A process for preparing 4-bromo-2fluoroaniline, which comprises brominating 2fluoroaniline in a solvent comprising dimethylformamide or dimethylacetamide.
3. A process for preparing 4-chloro-2fluoroaniline, which comprises chlorinating 2fluoroaniline in a solvent comprising dimethylformamide or dimethylacetamide.
4. A process according to claim 2 in which the brominating agent is dibromantin.
5. A process according to claim 1 substantially as described in the Example.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10506479A | 1979-12-19 | 1979-12-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2065654A true GB2065654A (en) | 1981-07-01 |
| GB2065654B GB2065654B (en) | 1983-03-30 |
Family
ID=22303855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8040291A Expired GB2065654B (en) | 1979-12-19 | 1980-12-16 | Halogenation of 2-fluoroaniline |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5697252A (en) |
| DE (1) | DE3046522A1 (en) |
| FR (1) | FR2482091A1 (en) |
| GB (1) | GB2065654B (en) |
| IT (1) | IT8050412A0 (en) |
| NL (1) | NL8006496A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0518374A2 (en) * | 1991-06-14 | 1992-12-16 | Dowelanco | A process for the preparation of alkyl 3-chloroanthranilates |
| US8217064B2 (en) | 2007-12-20 | 2012-07-10 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
| EP3798387A1 (en) | 2019-09-26 | 2021-03-31 | Sistemas Técnicos de Encofrados, S.A. | Support system for formworks |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3897057A (en) * | 1974-03-18 | 1975-07-29 | Donald D Pennington | Tethered ball baseball practice device |
| NL8006497A (en) * | 1979-12-19 | 1981-07-16 | Upjohn Co | PROCESS FOR PREPARING ARYL-PROPIONIC ACIDS. |
-
1980
- 1980-11-28 NL NL8006496A patent/NL8006496A/en not_active Application Discontinuation
- 1980-12-10 DE DE19803046522 patent/DE3046522A1/en not_active Withdrawn
- 1980-12-16 GB GB8040291A patent/GB2065654B/en not_active Expired
- 1980-12-18 FR FR8026941A patent/FR2482091A1/en active Granted
- 1980-12-18 IT IT8050412A patent/IT8050412A0/en unknown
- 1980-12-19 JP JP17915180A patent/JPS5697252A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0518374A2 (en) * | 1991-06-14 | 1992-12-16 | Dowelanco | A process for the preparation of alkyl 3-chloroanthranilates |
| EP0518374A3 (en) * | 1991-06-14 | 1993-04-28 | Dowelanco | A process for the preparation of alkyl 3-chloroanthranilates |
| US8217064B2 (en) | 2007-12-20 | 2012-07-10 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
| US8367863B2 (en) | 2007-12-20 | 2013-02-05 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
| US8664249B2 (en) | 2007-12-20 | 2014-03-04 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
| EP3798387A1 (en) | 2019-09-26 | 2021-03-31 | Sistemas Técnicos de Encofrados, S.A. | Support system for formworks |
| WO2021058849A1 (en) | 2019-09-26 | 2021-04-01 | Sistemas Técnicos de Encofrados, S.A | Support system for roof formworks |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2482091B1 (en) | 1984-10-26 |
| JPS5697252A (en) | 1981-08-05 |
| NL8006496A (en) | 1981-07-16 |
| IT8050412A0 (en) | 1980-12-18 |
| FR2482091A1 (en) | 1981-11-13 |
| GB2065654B (en) | 1983-03-30 |
| DE3046522A1 (en) | 1981-08-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |